Our laboratory has been also actively studying the roles of cytokines and their signaling pathways in liver diseases, focusing on the role of IL-6/STAT3 in fatty liver, liver inflammation and repair. We have previously demonstrated that IL-6 plays an important role in protecting against liver injury in several murine models of alcoholic liver injury, nonalcoholic fatty liver disease, fatty liver transplantation, and T cell hepatitis. It is believed that the action of IL-6 is mediated via activation of signal transducer and activator of transcription 3 (STAT3). [unreadable] By using immunohistochemistry analyses, we have demonstrated that phosphorylated STAT3 (STAT3 activation) are detected in hepatocytes, sinusoidal endothelial cells, bile duct-like cells, and inflammatory cells (macrophages, neutrophils etc) in human alcoholic cirrhotic livers (see Horiguchi et al., 2007). To understand the roles of STAT3 in alcoholic liver injury, we created liver-specific and macrophage/neutrophil-specific STAT3 knock out mice by crossing STAT3flox/flox mice with albumin-promoter Cre transgenic mice and lysozyme M-promoter Cre transgenic mice, respectively. Compared with wild-type mice, feeding hepatocyte-specific STAT3 knock out mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed macrophage/neutrophil-specific STAT3 knock out mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed hepatocyte-specific STAT3 knock out mice produced similar amounts of reactive oxygen species and tumor necrosis factor alpha, whereas Kupffer cells from macrophage/neutrophi-specific STAT3 knock out mice produced more reactive oxygen species and tumor necrosis factor alpha compared with wild-type controls. Our findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression (see Horiguchi et al., 2008). Currently, we are exploring the roles of endothelial cell- and macrophage/neutrophil-specific STAT3 in nonalcoholic fatty liver disease and liver regeneration. [unreadable] In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.